Characterization of iron metabolism in infants and children may be confounded by the diverse effects of developmental, genetic, and acquired influences on iron metabolism and laboratory measurements of iron status, especially in areas with intense perennial transmission of Plasmodium falciparum malaria. In the Pemba iron and folic acid supplementation trial, the coadministration of folic acid with iron is a further confounding factor. Because the design of the Pemba iron and folic acid supplementation study did not include a group that received iron supplementation without folic acid, the observed increase in serious adverse events cannot be ascribed unequivocally to iron alone, to folic acid alone, or to the combination of the two. In interpreting the results from the Pemba iron and folic acid supplementation trial, additional analyses of existing data from the trial and from earlier studies in the area could help clarify the roles of iron and folic acid.
LönnerdalBKelleherSL. Iron metabolism in infants and children. Food Nutr Bull2007;28:S491–9.
2.
DomellöfMLönnerdalBAbramsSAHernellO. Iron absorption in breast-fed infants: Effects of age, iron status, iron supplements, and complementary foods. Am J Clin Nutr2002;76:198–204.
3.
DeweyKGDomellöfMCohenRJLanda RiveraLHernellOLönnerdalB. Iron supplementation affects growth and morbidity of breast-fed infants: Results of a randomized trial in Sweden and Honduras. J Nutr2002;132:3249–55.
4.
IdjradinataPWatkinsWEPollittE. Adverse effect of iron supplementation on weight gain of iron-replete young children. Lancet1994;343:1252–4.
5.
NemethEGanzT. Regulation of iron metabolism by hepcidin. Annu Rev Nutr2006;26:323–42.
6.
BabittJLHuangFWWrightingDMXiaYSidisYSamadTACampagnaJAChungRTSchneyerALWoolfCJAndrewsNCLinHY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet2006;38:531–9.
7.
TruksaJPengHLeePBeutlerE. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA2006;103:10289–93.
8.
WangRHLiCXuXZhengYXiaoCZerfasPCoopermanSEckhausMRouaultTMishraLDengCX. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab2005;2:399–409.
9.
NiederkoflerVSalieRArberS. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest2005;115:2180–6.
10.
WrightingDMAndrewsNC. Interleukin-6 induces hepcidin expression through STAT3. Blood2006;108:3204–9.
RobertsDJCasals-PascualCWeatherallDJ. The clinical and pathophysiological features of malarial anaemia. Curr Top Microbiol Immunol2005;295:137–67.
13.
WambuaSMwangiTWKortokMUyogaSMMachariaAWMwacharoJKWeatherallDJSnowRWMarshKWilliamsTN. The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya. PLoS Med2006;3:e158.
14.
WeatherallDJMillerLHBaruchDIMarshKDoumboOKCasals-PascualCRobertsDJ. Malaria and the red cell. Hematology Am Soc Hematol Educ Program2002:35–57.
15.
WilliamsTN. Red blood cell defects and malaria. Mol Biochem Parasitol2006;149:121–7.
16.
Van VlierbergheHLangloisMDelangheJ. Haptoglobin polymorphisms and iron homeostasis in health and in disease. Clin Chim Acta2004;345:35–42.
17.
AtkinsonSHRockettKSirugoGBejonPAFulfordAO'ConnellMABaileyRKwiatkowskiDPPrenticeAM. Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2–2 genotype. PLoS Med2006;3:e172.
18.
KasvosveIGomoZANathooKJMatibePMudengeBLoyevskyMGordeukVR. Effect of ferroportin Q248H polymorphism on iron status in African children. Am J Clin Nutr2005;82:1102–6.
19.
DomellöfMDeweyKGLönnerdalBCohenRJHernellO. The diagnostic criteria for iron deficiency in infants should be reevaluated. J Nutr2002;132:3680–6.
20.
HentzeMWMuckenthalerMUAndrewsNC. Balancing acts: Molecular control of mammalian iron metabolism. Cell2004;117:285–97.
21.
MamiroPSKolsterenPRoberfroidDTatalaSOpsomerASVan CampJH. Feeding practices and factors contributing to wasting, stunting, and iron-deficiency anaemia among 3–23-month old children in Kilosa district, rural Tanzania. J Health Popul Nutr2005;23:222–30.
22.
HershkoC. Mechanism of iron toxicity. Food Nutr Bull2007;28:S500–9.
23.
HershkoCGrahamGBatesGWRachmilewitzEA. Non-specific serum iron in thalassaemia: An abnormal serum iron fraction of potential toxicity. Br J Haematol1978;40:255–63.
24.
RatledgeC. Iron metabolism and infection. Food Nutr Bull2007;28:S515–23.
25.
PapanikolaouGSamuelsMELudwigEHMacDonaldMLFranchiniPLDubéMPAndresLMacFarlaneJSakellaropoulosNPolitouMNemethEThompsonJRislerJKZaborowskaCBabakaiffRRadomskiCCPapeTDDavidasOChristakisJBrissotPLockitchGGanzTHaydenMRGoldbergYP. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet2004;36:77–82.
26.
RoettoAPapanikolaouGPolitouMAlbertiFGirelliDChristakisJLoukopoulosDCamaschellaC. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet2003;33:21–2.
27.
LanzaraCRoettoADaraioFRivardSFicarellaRSimardHCoxTMCazzolaMPipernoAGimenez-RoqueploAPGrammaticoPVoliniaSGaspariniPCamaschellaC. Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood2004;103:4317–21.
28.
PapanikolaouGTzilianosMChristakisJIBogdanosDTsimirikaKMacFarlaneJGoldbergYPSakellaropoulosNGanzTNemethE. Hepcidin in iron overload disorders. Blood2005;105:4103–5.
29.
De GobbiMRoettoAPipernoAMarianiRAlbertiFPapanikolaouGPolitouMLockitchGGirelliDFargionSCoxTMGaspariniPCazzolaMCamaschellaC. Natural history of juvenile haemochromatosis. Br J Haematol2002;117:973–9.
30.
VentoSCainelliFCesarioF. Infections and thalassaemia. Lancet Infect Dis2006;6:226–33.
31.
SazawalSBlackRERamsanMChwayaHMStoltzfusRJDuttaADhingraUKaboleIDebSOthmanMKKaboleFM. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: Community-based, randomised, placebo-controlled trial. Lancet2006;367:133–43.
32.
MetzJ. Folic acid metabolism and malaria. Food Nutr Bull2007;28:S540–9.
33.
GregsonAPloweCV. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev2005;57:117–45.
34.
GattonMLMartinLBChengQ. Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum. Antimicrob Agents Chemother2004;48:2116–23.
35.
MebrahtuTStoltzfusRJChwayaHMJapeJKSavioliLMontresorAAlbonicoMTielschJM. Low-dose daily iron supplementation for 12 months does not increase the prevalence of malarial infection or density of parasites in young Zanzibari children. J Nutr2004;134:3037–41.
36.
MugittuKAbdullaSFalkNMasanjaHFelgerIMshindaHBeckHPGentonB. Efficacy of sulfadoxine-pyrimethamine in Tanzania after two years as first-line drug for uncomplicated malaria: Assessment protocol and implication for treatment policy strategies. Malar J2005;4:55.
37.
CarterJYLoolpapitMPLemaOETomeJLNagelkerkeNJWatkinsWM. Reduction of the efficacy of antifolate antimalarial therapy by folic acid supplementation. Am J Trop Med Hyg2005;73:166–70.
38.
DzinjalamalaFKMachesoAKublinJGTaylorTEBarnesKIMolyneuxMEPloweCVSmithPJ. Blood folate concentrations and in vivo sulfadoxine-pyrimethamine failure in Malawian children with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg2005;72:267–72.
39.
MulengaMMalungaPBennettSThumaPShulmanCFieldingKGreenwoodB. Folic acid treatment of Zambian children with moderate to severe malaria anemia. Am J Trop Med Hyg2006;74:986–90.
40.
van HensbroekMBMorris-JonesSMeisnerSJaffarSBayoLDackourRPhillipsCGreenwoodBM. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Trans R Soc Trop Med Hyg1995;89:672–6.
41.
StoltzfusRJKvalsvigJDChwayaHMMontresorAAlbonicoMTielschJMSavioliLPollittE. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: Double blind, placebo controlled study. BMJ2001;323:1389–93.
42.
StoltzfusRJChwayHMMontresorATielschJMJapeJKAlbonicoMSavioliL. Low dose daily iron supplementation improves iron status and appetite but not anemia, whereas quarterly anthelminthic treatment improves growth, appetite and anemia in Zanzibari preschool children. J Nutr2004;134:348–56.
